The present invention relates to novel nitromethylthiobenzene derivatives, the processes for preparing them and to their therapeutic application, more particularly in the treatment or prevention of diabetic complications.
Diabetes is characterized by a high concentration of glucose in the blood. This glucose is normally metabolized by the enzyme hexokinase during the first step of glycolysis, resulting in degradation to pyruvate. When the glucose concentration is too high, the hexokinase becomes saturated, and a second glucose metabolization route comes into play; this is the polyol route which successively involves two enzymes: aldose reductase which converts the glucose into sorbitol, and sorbitol dehydrogenase which converts the sorbitol into fructose. In the case of diabetes, the excess glucose accelerates the formation of sorbitol, which tends to accumulate. This results in serious metabolic disturbances, such as, for example, an increase in osmotic pressure, which is liable to lead to tissue degeneration. Aldose reductase inhibitors are thus useful for treating or preventing some of the complications induced by diabetes.
Many products are described in the literature as being aldose reductase inhibitors which are active in vitro and in vivo. They are mainly hydantoin derivatives, succinimides and acetic acids. More recently, (phenylsulphonyl)nitromethane derivatives have appeared in European patent 304,190, and in particular the compound 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline in patent WO 90/08761. This compound has generated several derived series, such as the N-acylation products described in European patent 469,887 and the (oxamido- and ureido-phenylsulphonyl)hitromethanes described in European patent 469,889.
The present invention relates to nitromethylthiobenzene derivatives corresponding to the general formula 1, 
in which:
P represents
the radical (i): xe2x80x94(COxe2x80x94NH)mxe2x80x94SO2xe2x80x94R;
the radical (ii): 
or the radical (iii): 
R represents a radical chosen from phenyl, benzyl, diphenylmethyl, naphthyl, cycloalkylalkyl in which the alkyl part is C1-C4 and the cycloalkyl part is C3-C7, and styryl, the said radical optionally being substituted with one or more groups Z which may be identical or different, or alternatively
R represents a C3-C5 aromatic heterocyclic radical comprising 1 or 2 hetero atoms chosen from O, S and N, the said radical optionally being substituted with one or more groups Z, which may be identical or different, and optionally being fused to 1 or 2 phenyl rings which are optionally substituted with one or more groups Z, which may be identical or different; or alternatively
R represents C1-C4 alkyl optionally substituted with one or more halogen atoms, which may be identical or different, C3-C7 cycloalkyl or cyclo(C3-C7)alkyl(C1-C4)alkyl;
Z is chosen from a halogen atom, a C1-C4 alkyl, C1-C4 alkoxy, nitro, cyano, trifluoromethyl, trifluoro-methoxy, (C2-C5)alkylamino, (C1-C4)alkylsulphonyl, (C1-C4)alkylthio and phenyl group;
X represents a hydrogen or halogen atom;
m is 0 or 1;
n is 0, 1 or 2;
T1 and T2 represent, independently of each other, a hydrogen atom or a C1-C4 alkyl group,
u is 0 or 1;
A represents C1-C8 alkylene or the group 
y being an integer chosen from 0, 1, 2, 3 and 4; it being understood that when P represents the radical (ii), A can also represent a bond;
the tautomeric forms thereof and the addition salts thereof with pharmaceutically acceptable bases.
The term xe2x80x9cC1-C4 alkylxe2x80x9d denotes a linear or branched saturated hydrocarbon-based radical comprising from 1 to 4 carbon atoms. The alkoxy group consequently denotes the group alkyl-Oxe2x80x94 in which alkyl has the meaning indicated above.
As C3-C5 aromatic heterocycles comprising 1 or 2 hetero atoms chosen from O, S and N, mention may be made of furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, pyridine, pyridazine, pyrimidine and pyrazine, pyridine and thiophene being preferred.
As it is used herein, term xe2x80x9chalogenxe2x80x9d denotes a fluorine, bromine, chlorine or iodine atom.
Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. According to the invention, the cycloalkyalkyl group denotes an alkyl group substituted with a cycloalkyl group.
The term xe2x80x9calkylene radicalxe2x80x9d refers to a linear or branched divalent hydrocarbon-based saturated chain such as xe2x80x94CH2xe2x80x94; xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94; or xe2x80x94CH2xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94.
The group of formula: 
corresponds to one of the following formulae: 
in which y represents 0, 1, 2, 3 or 4.
According to the invention, when P represents the radical (ii) of formula: 
A is chosen from:
a bond, a C1-C8 alkylene radical, and
the group of formula 
in which y is an integer chosen from 0, 1, 2, 3 and 4.
Conversely, when P is xe2x80x94(COxe2x80x94NH)mxe2x80x94SO2xe2x80x94R or the radical (iii) of formula: 
then A is chosen from:
a C1-C8 alkylene radical, and
the group of formula: 
in which y is an integer chosen from 0, 1, 2, 3 and 4.
The possible tautomeric forms of the compounds of formula 1 form an integral part of the invention.
The addition salts, with pharmaceutically acceptable bases, of compounds of formula 1 in which X is a hydrogen atom and n is equal to 1 or 2 also form an integral part of the invention, for example an alkali or alkaline-earth metal salt, such as a sodium, potassium, calcium or magnesium salt, an aluminium salt, an ammonium salt or a salt of an organic base bearing a pharmaceutically acceptable cation.
A first group of preferred compounds consists of the compounds of formula 1 in which:
P represents xe2x80x94(COxe2x80x94NH)mxe2x80x94SO2xe2x80x94R
R represents a radical chosen from phenyl, diphenyl-methyl, naphthyl and styryl, the said radical optionally being substituted with one or more groups Z, which may be identical or different, or alternatively
R represents a C3-C5 aromatic heterocyclic radical comprising 1 or 2 hetero atoms chosen from O, S and N, the said radical optionally being substituted with one or more groups Z, which may be identical or different, and optionally being fused to 1 or 2 phenyl rings which are optionally substituted with one or more groups Z, which may be identical or different; or alternatively
R represents C1-C4 alkyl optionally substituted with one or more halogen atoms, which may be identical or different, C3-C7 cycloalkyl or cyclo(C3-C7)alkyl(C1-C4)-alkyl;
Z, X, m and n being as defined above for formula (1).
A second group of preferred compounds includes the compounds of formula 1 in which:
P represents xe2x80x94(COxe2x80x94NH)mxe2x80x94SO2xe2x80x94R,
R represents phenyl; phenyl substituted with one or more groups Z, which may be identical or different; benzyl; benzyl substituted with one or more groups Z which may be identical or different; C1-C4 alkyl optionally substituted with one or more halogen atoms, which may be identical or different; C3-C7 cycloalkyl; cyclo(C3-C7)alkyl(C1-C4)alkyl; styryl; thienyl; pyridyl; naphthyl; dibenzofuryl; or diphenylmethyl;
Z is chosen from a halogen atom, a C1-C4 alkyl, C1-C4 alkoxy, nitro, trifluoromethyl, trifluoromethoxy, (C2-C5)alkylamino, (C1-C4)alkylsulphonyl and phenyl group;
X, m and n being as defined above for formula (1).
Among this second group of preferred compounds, the compounds for which:
P represents xe2x80x94(COxe2x80x94NH)mxe2x80x94SO2xe2x80x94R,
R represents phenyl; phenyl substituted with one or more groups Z, which may be identical or different; benzyl; benzyl substituted with one or more groups Z which may be identical or different; methyl; C3-C7 cycloalkyl; cyclo(C3-C7)alkyl(C1-C4)alkyl; styryl; thienyl; pyridyl; naphthyl; dibenzofuryl; diphenylmethyl or 2,2,2-trifluoroethyl;
Z is chosen from fluoro, chloro, bromo, methyl, methoxy, nitro, trifluoromethyl, trifluoromethoxy, acetamido, methylsulphonyl and phenyl;
X represents hydrogen or chlorine;
m and n being as defined above for formula (1), are particularly advantageous.
A third group of preferred compounds consists of the compounds of formula 1 in which:
P represents xe2x80x94(COxe2x80x94NH)mxe2x80x94SO2xe2x80x94R,
R represents phenyl; phenyl substituted with one or more groups Z, which may be identical or different; methyl; C3-C7 cycloalkyl; cyclo(C3-C7)alkyl(C1-C4)alkyl; styryl; thienyl; pyridyl; naphthyl; dibenzofuryl; diphenylmethyl or 2,2,2-trifluoroethyl;
Z is chosen from fluoro, chloro, bromo, methyl, methoxy, nitro, trifluoromethyl, trifluoromethoxy, acetamido, methylsulphonyl and phenyl;
X represents hydrogen or chlorine;
m and n being as defined above for formula (1).
A fourth group of preferred compounds consists of the compounds of formula (1) in which:
P represents: 
A represents a bond or C1-C8 alkylene,
u, n, X, T1 and T2 being as defined above for formula (1).
A fifth group of preferred compounds consists of the compounds of formula (1) in which:
P represents: 
A represents the group 
n, X, y, T1 and T2 being as defined above for formula (1).
Compounds which are particularly preferred are the following:
N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]benzenesulphonamide;
3,4-difluoro-N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]benzenesulphonamide;
3-bromo-N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]benzenesulphonamide;
N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-2-(trifluoromethyl)benzenesulphonamide;
N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-4-fluorobenzenesulphonamide;
N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-3-fluorobenzenesulphonamide;
N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]phenylmethanesulphonamide; 2,3-difluoro-N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]benzenesulphonamide; 3,5-difluoro-N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]benzenesulphonamide;
N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-2-fluorobenzenesulphonamide, and the following compounds:
N,Nxe2x80x2-bis[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-1,5-pentanediamide;
N,Nxe2x80x2-bis[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-1,8-octanediamide;
N,Nxe2x80x2-bis[4-[(nitromethyl)sulphonyl]phenyl]-1,5-pentanediamide;
N,Nxe2x80x2-bis[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-ethanediamide;
N,Nxe2x80x2-bis[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-urea;
N,Nxe2x80x2-bis[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-1,4-butanediamide;
N,Nxe2x80x2-bis[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-1,3-propanediamide;
N,Nxe2x80x2-bis[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-1,3-benzenedisulphonamide;
N,Nxe2x80x2-bis[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-1,3-benzenedimethane sulphonamide.
The compounds of the invention are prepared according to the following methods:
(A) When P represents xe2x80x94(COxe2x80x94NH)mxe2x80x94SO2xe2x80x94R, X is a hydrogen atom, m is equal to 0 and n is equal to 2, a sulphonyl chloride of formula RSO2Cl, R having the meanings defined above, is reacted with the compound of formula 2, 
in which T1 and T2 are as defined above for (1), in the presence of a suitable base.
The reaction is preferably carried out in a solvent, for example a polar aprotic solvent such as tetrahydrofuran at a temperature between 10xc2x0 C. and the boiling point of the solvent.
As bases which are particularly suitable, mention may be made of calcium carbonate (method A1) or pyridine (method A2).
(B) When P represents xe2x80x94(COxe2x80x94NH)mxe2x80x94SO2xe2x80x94R, X is a halogen atom, preferably chlorine, m is equal to 0 and n is equal to 2, the appropriate N-halosuccinimide is reacted with a compound of the formula 3 
in which R, T1 and T2 have the meanings defined above for (1), in the presence of a free-radical generator such as 2,2xe2x80x2-azobisisobutyronitrile.
The reaction is preferably carried out in a solvent, for example a halohydrocarbon such as carbon tetrachloride, maintained at reflux.
(C) When P represents xe2x80x94(COxe2x80x94NH)mxe2x80x94SO2xe2x80x94R, X is a hydrogen atom, m is equal to 1 and n is equal 2, a sulphonyl isocyanate of formula Rxe2x80x94SO2xe2x80x94Nxe2x95x90Cxe2x95x90O, R having the meanings defined above, is reacted with the compound of formula 2 defined above.
The reaction is preferably carried out in a solvent, for example a halohydrocarbon such as methylene chloride, at a temperature in the region of room temperature.
(D) When P represents xe2x80x94(COxe2x80x94NH)mxe2x80x94SO2xe2x80x94R, X is a hydrogen atom and m and n are equal to 0, a sulphonyl chloride of formula RSO2Cl, R having the meanings defined above, is reacted with the compound of formula 10, 
in which T1 and T2 are as defined for (1), in the presence of a suitable base.
The reaction is preferably carried out in a solvent, for example a polar aprotic solvent such as tetrahydrofuran, at a temperature in the region of room temperature. A particularly suitable base is, for example, calcium carbonate.
(E) When P represents xe2x80x94(COxe2x80x94NH)mxe2x80x94SO2xe2x80x94R, X is a hydrogen atom, m is equal to 0 and n is equal to 1, an oxidizing agent such as m-chloroperbenzoic acid is reacted with a compound of formula 4, 
in which R, T1 and T2 have the meanings defined above.
The process is preferably performed in a solvent, for example chloroform, at a temperature in the region of room temperature.
(F) When P represents the radical (ii) of formula: 
u is 1, X represents a hydrogen atom and n is equal to 2, the dichloride of formula 5 below: 
is reacted with at least two molar equivalents of compound of formula 2 defined above, in the presence of a base.
The reaction is preferably carried out in a solvent, for example a polar aprotic solvent such as tetrahydrofuran, at a temperature of between 10xc2x0 C. and the boiling point of the solvent.
As bases which are particularly suitable, mention may be made of calcium carbonate (method F1) or pyridine (method F2).
The molar ratio of the compound of formula 2 to the compound of formula 5 is preferably between 2 and 4. However, it should be understood that a larger amount of aniline derivative can be used without any adverse effect.
(G) When P represents the radical (iii) of formula: 
X represents a hydrogen atom and n is equal to 2, the sulphonyl dichloride of formula 6 below: 
is reacted with at least two molar equivalents of compound of formula 2 defined above, in the presence of a base.
Here also, calcium carbonate (method G1) and pyridine (method G2) constitute preferred examples of suitable bases.
The reaction is advantageously carried out in a polar aprotic solvent at between 10xc2x0 C. and the boiling point of the solvent.
It generally suffices to react 2 to 4 molar equivalents of compound of formula 2 with dichloride of formula 6, although a larger amount does not harm the reaction.
(H) When P represents the radical (ii) of formula: 
in which u is zero, X represents a hydrogen atom and n is equal to 2, trichloromethyl chloroformate is reacted with at least two molar equivalents of compound of formula 2 defined above in the presence of base.
The reaction is preferably carried out in a polar aprotic solvent such as tetrahydrofuran, at a temperature of between 10xc2x0 C. and the boiling point of the solvent.
As a base which is particularly suitable, mention may be made of calcium carbonate. The molar ratio of the compound of formula 2 to the trichloromethyl chloroformate is preferably between 2 and 4.
The intermediate compound of formula 2 defined above is obtained as described in patent WO 90/08761 by basic hydrolysis of the compound of formula 9. The latter compound was prepared according to the following method, in particular using the novel reaction of nitromethanesodium with the aryl thiocyanate 7 to give the compound 8: 
The intermediate compound of formula 10 is obtained by basic hydrolysis of the compound of formula 8. 
One specific embodiment of this process consists in preparing 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline, which corresponds to the compound of formula 2 in which T1 and T2 represent xe2x80x94CH3.
The inhibition of the enzyme aldose reductase and the reduction of the accumulation of sorbitol can be demonstrated in standardized laboratory tests below:
1) In Vitro Study: Inhibition of Aldose Reductase
The aldose reductase used is obtained from the lenses of male Wistar rats according to a modification of the method by S. Hayman et al. (Journal of Biological Chemistry 240, p. 877, 1965). The enzymatic extract is diluted in a phosphate buffer in the presence of NADPH and various concentrations of the test products. The reaction is triggered with L-glyceraldehyde and the rate of reaction is measured by monitoring the disappearance of the NADPH by spectrophotometry at 340 nm. The rate of reaction is calculated for each concentration of products, and the concentration required for a 50% reduction in the rate of reaction (IC50) is then evaluated by linear interpolation.
2) In Vivo Study: Reduction of the Accumulation of Sorbitol
Male Wistar rats weighing from 200 to 250 g are made diabetic by intravenous injection of streptozotocin (60 mg/kg). They then receive an oral treatment of the test products, in the form of a suspension, 4 hours, 30 hours and 52 hours after the injection of streptozotocin. 18 hours after the final oral treatment, the rats are sacrificed and decapitated and their sciatic nerves are then removed. After extraction, the level of sorbitol in the nerves is measured according to the enzymatic method described by H. J. Bergmeyer (Methods of enzymatic analysis, H. U. Bergmeyer ed., Academic Press New York 3, p. 1323, 1974). The percentage of protection is calculated for each product relative to the batch of diabetic animals, taking into account the level of sorbitol in the sciatic nerves of non-diabetic rats.
By way of example, the results obtained for some of the test products are given in the table below:
The compounds of the invention can be used as medicinal products as aldose reductase inhibitors, and in particular in the treatment of diabetic complications such as cataracts, retinopathies, neuropathies, nephropathies and certain vascular diseases.
These medicinal products can be administered orally in the form of immediate-release or controlled-release tablets, gelatin capsules or granules, intravenously in the form of an injectable solution, transdermally in the form of an adhesive transdermal device, or topically in the form of eyedrops, a solution, cream or gel.
The active principle is combined with various pharmaceutical excipients. The daily doses can range from 5 mg to 200 mg of active principle.
A number of pharmaceutical formulations are given below as non-limiting examples:
The examples which follow illustrate the invention in a non-limiting manner.
The following abbreviations have been used in the nuclear magnetic resonance (NMR) data: s for singlet, d for doublet, t for triplet, q for quartet and m for complex multiplet; the chemical shifts xcex4 are expressed in ppm.